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Adjunctive capecitabine stakes out role in treatment of triple-negative breast cancer

Jairia Dela Cruz
14 Aug 2017

Capecitabine appears to provide additional survival benefit in triple-negative breast cancer (TNBC) patients treated with standard chemotherapy, significantly improving disease-free survival (DFS) and overall survival (OS) but potentially increasing adverse events consistent with the drug’s known toxicity profile, according to a meta-analysis.

“Our findings support the underlying rationale for combination chemotherapy, in that individual drugs that work by different mechanisms may decrease the likelihood of drug resistance, reducing the risk of recurrence,” said lead investigator Dr Akina Natori from the Princess Margaret Cancer Centre in Toronto, Ontario, Canada.

Pooling data from eight randomized controlled trials (n=9,302 patients) comparing the effect of standard chemotherapy with or without capecitabine in the neoadjuvant or adjuvant setting on survival, Natori and colleagues found that capecitabine did not influence DFS (hazard ratio [HR], 0.99; p=0.93) or OS (HR, 0.90; p=0.36) in unselected patients. [Eur J Cancer 2017;77:40–47]

However, a significant improvement in DFS was observed when capecitabine was given as an adjunct to standard treatment than in place of standard treatment (HR, 0.92 vs 1.62; p=0.002 for interaction). The addition of capecitabine to standard chemotherapy particularly improved DFS in TNBC vs non-TNBC patients (HR, 0.72 vs 1.01; p=0.02 for interaction) in a subgroup analysis.

Meta-regression also showed that adjunctive capecitabine was associated with better OS in trials that included higher proportions of patients with TNBC (p=0.007).

“Unsurprisingly, the addition of capecitabine to standard adjuvant chemotherapy increases toxicity in keeping with the well-recognised toxicity profile of this drug, which is generally manageable in clinical practice,” noted Natori.

Capecitabine substantially increased the frequency of grade 3/4 diarrhoea (odds ratio [OR], 2.33; p<0.001) and hand-foot syndrome (OR, 8.08; p<0.001), and resulted in more frequent treatment discontinuation (OR, 3.80; p<0.001).

“Given the benefit observed in patients with TNBC, we reason that the currently available data are sufficient to consider the addition of capecitabine to standard therapy, particularly for high-risk patients,” Natori stated, while acknowledging that the pooled analysis of subgroups from trials that were not powered to detect significance in the TNBC subgroup might be a potential limitation.

Natori pointed out that although the eight trials included in the analysis evaluated a variety of regimens and there is no clearly superior strategy, “a postneoadjuvant approach as studied in CREATE-X is especially attractive, since it does not affect the ability to deliver the standard anthracycline/taxane chemotherapy, and permits selection of the group at greatest risk: those with pathologic residual invasive disease who exhibit very high rates of early recurrence.”

Level 1 evidence from CREATE-X

In a perspective piece, Drs Jo Anne Zujewski and Lawrence Rubinstein from the National Cancer Institute, Bethesda, Maryland, USA, highlighted that the CREATE-X trial provides level 1 evidence that adjuvant capecitabine is superior to no additional therapy in patients who are resistant to anthracycline and taxane-based therapy. [NPJ Breast Cancer 2017;doi:10.1038/s41523-017-0029-3]

Results from the CREATE-X involving 910 women with early stage breast cancer who received standard preoperative chemotherapy and had residual invasive breast cancer at the time of surgery showed that the survival outcomes at 5 years of follow-up were strongly positive with capecitabine vs no additional therapy (DFS, 82.8 vs 79 percent; HR, 0.70; p=0.005; OS, 89.2 vs 83.9 percent; HR, 0.60; p=0.001). The most dramatic results were seen in the subset of patients with TNBC (HR, 0.58; 0.39 to 0.87). [N Engl J Med 2017;376:2147–2159]

“These results were surprising given [that] previously reported trials did not show a benefit in using adjuvant capecitabine,” Zujewski and Rubinstein said. [J Clin Oncol 2011;30;11–18; Clin Cancer Res 2015;21:4305–4311; J Clin Oncol 2011;30:930–935; J Clin Oncol 2012;30:930–935]

Conducted in Japan and Korea, CREATE-X raised the possibility that differences in the Asian and non-Asian populations could explain the positive findings, as well as suggested that its results might not be applicable to a non-Asian population.

Zujewski and Rubinstein pointed to the known pharmacogenetic differences between Asian (Japanese) and Caucasian patients, with Japanese patients reported to have approximately 36 percent lower Cmax and 24 percent area under curve following an oral administration of 825 mg/m2 capecitabine twice daily for 14 days. This may explain why Asian patients tolerated an oral dose (2,500 mg/m2) that is 25 percent higher than the oral dose commonly used in the United States.

“In patients with residual disease in the breast or lymph nodes after neoadjuvant chemotherapy, survival may be improved with additional chemotherapy… It is appropriate to discuss the addition of capecitabine to patients who would have met the eligibility criteria of CREATE-X,” they said.

Additionally, it must be noted that “the recommended dose of capecitabine for treatment of metastatic HER-2-negative breast cancer (2,500 mg/m2/day in divided doses for 14 days) is associated with significant toxicity in non-Asian populations,” they added.

Finally, whether or not adjuvant capecitabine represents a new standard of care for patients with residual disease after neoadjuvant chemotherapy remains controversial, Zujewski and Rubinstein said.  “Not all experts agree that a single trial providing level 1 evidence is sufficient, especially if the ethnicities of the tested populations differ. Once the data are published in a peer-reviewed publication, this issue will be readdressed.” 

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